The subject of the present invention is a novel method for the preparation, by crystallization from isopropyl ether, of (R)-4-[(3,4-dichlorobenzoyl)amino]-5-[(3-methoxypropyl)-pentylamino]-5-oxo-pentanoic acid (dexloxiglumide, CR 2017); molecular formula: C21H30Cl2N2O5; CAS Registry Number: 119818-90-2.
Dexloxiglumide, the compound which is the subject of the present invention, has been shown to possess potent antagonistic activity towards the type-1 cholecystokinin (CCK1) receptor. Dexloxiglumide can therefore be used advantageously for the treatment of various diseases in man, such as some pathological conditions of the gastrointestinal tract, for example, irritable colon syndrome, non-ulcerative dyspepsia, biliary colic and dyskinesia, gastro-oesophageal reflux, pancreatitis or, more generally, gastrointestinal motility disorders.
The preparation and some pharmacological activities of this compound have already been described, for example, in U.S. Pat. No. 5,602,179.
The final purification of the product was performed by crystallization from an H2O/alcohol mixture in the ratio of 2:1 (v/v). This purification enabled a chemically pure compound, that is, with a chemical purity and an optical purity greater than 99.5%, to be obtained.
However, the rheological characteristics of the product thus obtained where wholly unsatisfactory since the crystal had poor flowability properties, preventing its advantageous use for the preparation of oral pharmaceutical forms such as, for example, tablets.
Moreover, trying to vary the relative proportions of the two components of the aqueous/alcoholic mixture did not improve the characteristics of the raw material which, on the contrary, still had mixtures of polymorphs.